Clustered Mendelian Randomization analyses identifies distinct and opposing pathways in the causal association between insulin-like growth factor-1 and type 2 diabetes mellitus

Aims/hypothesis: There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of type 2 diabetes. Here, we investigated the association between IGF-1 and type 2 diabetes using a combination of multivariable-adjusted and (clustered) Mendelian Randomization (MR) analyses in the UK Biobank. Methods: We conducted Cox proportional hazard analyses in 451,232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13,247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent SNPs associated with IGF-1. Given the heterogeneity between the causal estimates of individual instruments (P-value for Q statistic=4.03e-145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by overrepresentation analyses. Results: In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes (HR: 1.31; CI: 1.23-1.39). In contrast, in the two-sample MR analyses, higher genetically-influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of causal effect estimates, six clusters associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth-hormone signaling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity. Conclusion: The IGF-1 associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of causal effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.

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Alcohol use and cardiometabolic risk in the UK Biobank: a Mendelian randomization study

10.1101/2020.11.10.376400 ◽

2020 ◽

Author(s):

Joanna Lankester ◽

Daniela Zanetti ◽

Erik Ingelsson ◽

Themistocles L. Assimes

Keyword(s):

Type 2 Diabetes ◽

Alcohol Consumption ◽

Alcohol Use ◽

Mendelian Randomization ◽

Lower Amount ◽

Cardiometabolic Health ◽

Uk Biobank ◽

The Uk ◽

Cardiometabolic Traits

AbstractObservational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. We found carriers of the ADH1B Arg47His variant (rs1229984) reported a 26% lower amount of alcohol consumption compared to non-carriers. In our one-sample, two-stage least squares analyses of the UK Biobank using rs1229984 as an instrument, one additional drink/day was associated with statistically significant elevated level of systolic blood pressure (3.0 mmHg), body mass index (0.87 kg/m^2), waist circumference (1.3 cm), body fat percentage (1.7%), low-density lipoprotein levels in blood (0.16 mmol/L), and the risk of myocardial infarction (OR=1.50), stroke (OR=1.52), any cardiovascular disease (OR=1.43), and all-cause mortality (OR=1.41). Conversely, increasing use of alcohol was associated with reduced levels of triglycerides (−0.059 mmol/L) and HbA1C (−0.42 mmol/mol) in the blood, the latter possibly a consequence of a statistically elevated mean corpuscular volume among ADH1B Arg47His carriers. Stratifications by sex and smoking revealed a pattern of more harm of alcohol use among men compared to women, but no consistent difference by smoking status. Men had an increased risk of heart failure (OR = 1.76), atrial fibrillation (OR = 1.35), and type 2 diabetes (OR = 1.31) per additional drink/day. Using summary statistics from external datasets in 2-sample analyses for replication, we found causal associations between alcohol and obesity, stroke, ischemic stroke, and type 2 diabetes. Our results are consistent with an overall harmful effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

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Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1002982 ◽

2019 ◽

Vol 16 (12) ◽

pp. e1002982 ◽

Cited By ~ 6

Author(s):

Michael Wainberg ◽

Anubha Mahajan ◽

Anshul Kundaje ◽

Mark I. McCarthy ◽

Erik Ingelsson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

Uk Biobank ◽

The Uk

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The effect of BMI and type 2 diabetes on socioeconomic status: a two-sample multivariable Mendelian randomization study

10.2337/figshare.13348040.v1 ◽

2021 ◽

Author(s):

Sara Pedron ◽

Christoph F Kurz ◽

Lars Schwettmann ◽

Michael Laxy

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Causal Effect ◽

Univariate Analysis ◽

Causal Link ◽

Marginal Effect ◽

Nucleotide Polymorphisms ◽

Socioeconomic Outcomes ◽

The Uk

OBJECTIVE To assess the independent causal effect of BMI and type 2 diabetes (T2D) on socioeconomic outcomes applying two-sample Mendelian randomization (MR) analysis. RESEARCH DESIGN AND METHODS We carried out univariate and multivariate two-sample MR to jointly assess the effect BMI and T2D on socioeconomic outcomes. We used overlapping genome-wide significant single nucleotide polymorphisms (SNPs) for BMI and T2D as instrumental variables. Their causal impact on household income and regional deprivation was assessed using summary-level data from the UK Biobank. RESULTS In the univariate analysis, higher BMI was related with lower income (marginal effect of 1-SD increase in BMI [β=-0.092 (95% CI: -0.138; -0.047)] and higher deprivation [β=0.051 (95% CI: 0.022; 0.079)]. In the multivariate MR, the effect of BMI controlling for diabetes was slightly lower for income and deprivation. Diabetes was not associated with these outcomes. CONCLUSIONS High BMI, but not diabetes, shows a causal link with socioeconomic outcomes.

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The effect of BMI and type 2 diabetes on socioeconomic status: a two-sample multivariable Mendelian randomization study

10.2337/figshare.13348040 ◽

2021 ◽

Author(s):

Sara Pedron ◽

Christoph F Kurz ◽

Lars Schwettmann ◽

Michael Laxy

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Causal Effect ◽

Univariate Analysis ◽

Causal Link ◽

Marginal Effect ◽

Nucleotide Polymorphisms ◽

Socioeconomic Outcomes ◽

The Uk

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Birth weight, BMI in adulthood and latent autoimmune diabetes in adults: A Mendelian randomization study

10.1101/2021.10.25.21265464 ◽

2021 ◽

Author(s):

Yuxia Wei ◽

Yiqiang Zhan ◽

Josefin E. Lofvenborg ◽

Tiinamaija Tuomi ◽

Sofia Carlsson

Keyword(s):

Type 2 Diabetes ◽

Birth Weight ◽

Low Birth Weight ◽

Mendelian Randomization ◽

Autoimmune Diabetes ◽

Sensitivity Analyses ◽

Uk Biobank ◽

Latent Autoimmune Diabetes ◽

The Uk

Aims: Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birth weight and adult overweight/obesity. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomization (MR) design. In addition, we wanted to compare results for LADA and type 2 diabetes. Methods: We identified 129 SNPs as instrumental variables (IVs) for birth weight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2,634 cases and 5,947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. Results: Genetically determined birth weight was inversely associated with LADA (OR per SD [~500 g] decrease in birth weight: 2.02, 95% CI: 1.37-2.97). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [~4.8 kg/m2] increase in BMI: 1.40, 95% CI: 1.14-1.71). Results persisted in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birth weight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. Conclusions/ interpretation: This study provides genetic support for a causal link between low birth weight, adult overweight/obesity, and LADA.

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Does Obesity Cause Thyroid Cancer? A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa250 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2398-e2407

Author(s):

Jonathan Mark Fussey ◽

Robin N Beaumont ◽

Andrew R Wood ◽

Bijay Vaidya ◽

Joel Smith ◽

...

Keyword(s):

Type 2 Diabetes ◽

Thyroid Cancer ◽

Thyroid Disease ◽

Observational Studies ◽

Mendelian Randomization ◽

European Ancestry ◽

Uk Biobank ◽

Reverse Causality ◽

The Uk

Abstract Background The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. Methods We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. Results Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). Conclusions Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.

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Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype

10.1101/837013 ◽

2019 ◽

Author(s):

Yann C. Klimentidis ◽

Amit Arora ◽

Michelle Newell ◽

Jin Zhou ◽

Jose M. Ordovas ◽

...

Keyword(s):

Type 2 Diabetes ◽

Mendelian Randomization ◽

Uk Biobank ◽

Alcoholic Fatty Liver ◽

Genome Wide ◽

Using Data ◽

Underlying Mechanisms ◽

The Uk ◽

Alcoholic Fatty Liver Disease

AbstractAlthough hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that LDL-C was negatively associated with T2D (OR=0.43[0.41, 0.45] per mmol/L unit of LDL-C), despite positive associations of LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. Finally, two-sample Mendelian randomization analyses suggest that low LDL-C causes T2D, although causal interpretations are challenging due to pleiotropy. Our findings extend our current understanding of the higher T2D risk among individuals with low LDL-C, and of the underlying mechanisms, including those underlying the diabetogenic effect of LDL-C-lowering medications.

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Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study

npj Genomic Medicine ◽

10.1038/s41525-021-00189-6 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Shuai Yuan ◽

Edward L. Giovannucci ◽

Susanna C. Larsson

Keyword(s):

Type 2 Diabetes ◽

Chronic Pancreatitis ◽

Alcohol Consumption ◽

Mendelian Randomization ◽

Gallstone Disease ◽

Smoking Initiation ◽

Disease Type ◽

Uk Biobank ◽

Increased Risk

AbstractWe conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p < 5 × 10−8 were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.

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Night Shift Work, Genetic Risk, and Type 2 Diabetes in the UK Biobank

Diabetes Care ◽

10.2337/dc17-1933 ◽

2018 ◽

Vol 41 (4) ◽

pp. 762-769 ◽

Cited By ~ 59

Author(s):

Céline Vetter ◽

Hassan S. Dashti ◽

Jacqueline M. Lane ◽

Simon G. Anderson ◽

Eva S. Schernhammer ◽

...

Keyword(s):

Type 2 Diabetes ◽

Shift Work ◽

Genetic Risk ◽

Night Shift ◽

Uk Biobank ◽

Night Shift Work ◽

The Uk

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Abstract 021: C-reactive Protein Partially Mediates The Inverse Association Between Coffee Consumption And Risk Of Type 2 Diabetes: Findings From The UK Biobank And The Rotterdam Studies

Circulation ◽

10.1161/circ.143.suppl_1.021 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Carolina Ochoa-Rosales ◽

Niels van der Schaft ◽

Kim V Braun ◽

Frederick Ho ◽

Fanny Petermann ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coffee Consumption ◽

Inverse Association ◽

Statistical Regression ◽

Uk Biobank ◽

C Reactive Protein ◽

Coffee Intake ◽

Reactive Protein ◽

The Uk

Background: Coffee intake has been linked to lower type 2 diabetes (T2D) risk. We hypothesized this may be mediated by coffee’s effects on inflammation. Methods: Using participants from the UK Biobank (UKB n=145370) and Rotterdam Study (RS n=7172) cohorts, we studied associations of coffee intake with incident T2D; longitudinally measured insulin resistance (HOMA IR); serum levels of inflammation markers; and the mediating role of inflammation. Statistical regression models were adjusted for sociodemographic, lifestyle and health factors. Results: The median follow up was 7 (UKB) and 9 (RS) years. An increase of one coffee cup/day was associated with 4-6% lower T2D risk (RS HR=0.94 [95% CI 0.90; 0.98]; UKB HR=0.96 [0.94; 0.98]); lower HOMA IR (RS β=-0.017 [-0.024; -0.010]); with lower C reactive protein (CRP) and higher adiponectin (Figure1). Consumers of filtered coffee had the lowest T2D risk (UKB HR=0.88 [0.83; 0.93]). CRP levels mediated 9.6% (UKB) and 3.4% (RS) of the total effect of coffee on T2D (Figure 1). Conclusions: We suggest that coffee’s beneficial effects on lower T2D risk are partially mediated by improvements in systemic inflammation.Figure 1. a CRP and a adiponectin refer to the effect of coffee intake on CRP and adiponectin levels. a CRP RS : β=-0.014 (-0.022; -0.005); UKBB a CRP UKB : β=-0.011 (-0.012; -0.009) and RS a adiponectin : β=0.025 (0.007; 0.042). b CRP and b adiponectin refer to the effect of coffee related levels in CRP and adiponectin on incident T2D, independent of coffee. RS b CRP : HR=1.17 (1.04; 1.31); UKB b CRP : HR=1.45 (1.37; 1.54); and b adiponectin : HR=0.58 (0.32; 0.83). c′ refers to coffee’ effect on T2D going directly or via others mediators. UKB c′ independent of CRP : HR=0.96 (0.94; 0.99); RS c′ independent of CRP : HR=0.94 (0.90; 0.99); and RS c′ independent of CRP+adiponectin : HR=0.90 (0.80; 1.01). Coffee related changes in CRP may partially explain the beneficial link between coffee and T2D, mediating a 3.4% (0.6; 4.8, RS) and 9.6% (5.7; 24.4, UKB). Evidence of mediation was also found for adiponectin.

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